Multi-dimensional high resolution nuclear magnetic resonance (NMR) spectroscopy and restrained molecular dynamics will be used to define the three-dimensional structure of antisense, sense and ribozyme oligonucleotide agents, and nucleic acid-agent complexes targeted towards the human immunodeficiency (AIDS) virus. Diasteromerically pure phosphorothioates and phosphorodithioate oligonucleotide analogues will be synthesized and the three-dimensional structure of their complexes with complementary single-stranded oligonucleotides in duplex, ribozyme and three-stranded junctions will be determined to understand the in vitro and in vivo biological activities that will also be obtained. The investigators will also design, synthesize and structurally characterize sense (or decoy) oligonucleotide analogues targeted to HIV-1 reverse transcriptase. Various RNA and DNA agents will be synthesized using established synthetic organic methods. They will take an integrated approach towards the rational design of agents targeted towards HIV utilizing NMR, computational biochemistry, and molecular modeling of nucleic acid agents. NMR spectroscopy will provide an important probe of the molecular structure and dynamics of these macromolecules and their target complexes. Finally they will utilize folate receptor mediated endocytosis to effectively deliver backbone modified, liposomal encapsulated agents targeted to the epidermal growth factor receptor directly into the cytoplasm of human cells. This should help avoid problems associated with most other delivery methods that end up compartmentalizing the agents, often into the lysosomes where they are degraded. Ultimately the investigators hope to rationally design and construct agents to inhibit HIV-1 proliferation and gene expression.